Coexistence of phenylketonuria and tyrosinemia type 3: challenges in the dietary management

Arzu Selamioğlu; Tuğba Kozanoğlu; İlknur Hacıoğlu; Mehmet Cihan Balcı; Meryem Karaca; Asuman Gedikbaşı; Bülent Uyanık; Gülden Gökçay

doi:10.1515/jpem-2024-0378

Article

Coexistence of phenylketonuria and tyrosinemia type 3: challenges in the dietary management

Arzu Selamioğlu , Tuğba Kozanoğlu , İlknur Hacıoğlu , Mehmet Cihan Balcı , Meryem Karaca , Asuman Gedikbaşı , Bülent Uyanık and Gülden Gökçay

Published/Copyright: January 10, 2025

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Journal of Pediatric Endocrinology and Metabolism Volume 38 Issue 3

Abstract

Objectives

Phenylketonuria (PKU) and tyrosinemia type 3 (HT3) are both rare autosomal recessive disorders of phenylalanine-tyrosine metabolism. PKU is caused by a deficiency in phenylalanine hydroxylase (PAH), leading to elevated phenylalanine (Phe) and reduced tyrosine (Tyr) levels. HT3, the rarest form of tyrosinemia, is due to a deficiency in 4-hydroxyphenylpyruvate dioxygenase (HPD).

Case presentation

We report a 5-year-old girl diagnosed with both PKU and HT3. She presented with elevated Phe levels in neonatal screening, and subsequent biochemical tests revealed both hyperphenylalaninemia and elevated Tyr levels. Genetic analysis confirmed the diagnoses, identifying homozygous mutations in both the PAH and HPD genes. Dietary management to maintain optimal Phe and Tyr levels proved to be challenging due to the presence of these two coexisting pathologies especially during infections and due to dietary non-compliance, necessitating frequent adjustments in the treatment strategy.

Conclusions

This case highlights the importance of considering multiple metabolic disorders in patients with unexplained clinical and biochemical findings. Early diagnosis and stringent dietary management are crucial for preventing neurological damage and ensuring favorable outcomes in patients with concurrent metabolic disorders.

Keywords: phenylketonuria; tyrosinemia type 3; coexistence; dietary management

Corresponding author: Arzu Selamioğlu, MD, Division of Pediatric Metabolic Diseases, Bağcılar Training and Research Hospital, Istanbul, Türkiye; and Department of Rare Diseases, Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Türkiye, E-mail: arzuceyln@hotmail.com

Research ethics: The study was exempted from review because of being a case report.
Informed consent: Informed consent was obtained from all individuals included in this study, or their legal guardians or wards.
Author contributions: Arzu Selamioğlu conceptualized and drafted the initial manuscript, analyzed the data, and revised the manuscript. Tuğba Kozanoğlu and İlknur Hacıoğlu contributed to data collection and chart review. Mehmet Cihan Balci and Meryem Karaca designed the data collection instruments, and critically reviewed and revised the manuscript. Asuman Gedikbaşı and Bulent Uyanık conducted the genetic analysis and interpretation. Gülden Gökçay critically supervised the whole study process. All authors read and approved the final manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The authors state no conflict of interest.
Research funding: None declared.
Data availability: The raw data can be obtained on request from the corresponding author.

References

1. Sharman, R, Sullivan, K, Young, R, McGill, J. A preliminary investigation of the role of the phenylalanine: tyrosine ratio in children with early and continuously treated phenylketonuria: toward identification of “safe” levels. Dev Neuropsychol 2009;35:57–65. https://doi.org/10.1080/87565640903325725.Search in Google Scholar PubMed

2. Beyzaei, Z, Nabavizadeh, S, Karimzadeh, S, Geramizadeh, B. The mutation spectrum and ethnic distribution of non-hepatorenal tyrosinemia (types II, III). Orphanet J Rare Dis 2022;17:1–6. https://doi.org/10.1186/s13023-022-02579-0.Search in Google Scholar PubMed PubMed Central

3. Heylen, E, Scherer, G, Vincent, MF, Marie, S, Fischer, J, Nassogne, MC. Tyrosinemia Type III detected via neonatal screening: management and outcome. Mol Genet Metabol 2012;107:605–7. https://doi.org/10.1016/j.ymgme.2012.09.002.Search in Google Scholar PubMed

4. Endo, F, Kitano, A, Uehara, I, Nagata, N, Matsuda, I, Shinka, T, et al.. A new variant form of hypertyrosinaemia due to 4-hydroxyphenylpyruvic acid oxidase deficiency. J Inherit Metab Dis 1982;5:237–8. https://doi.org/10.1007/bf02179153.Search in Google Scholar PubMed

5. Han, D, Wang, L, Zhao, C, Li, J, Huang, C, Song, W, et al.. Novel HPD mutation p. A244V compound with p. T219M causing tyrosinemia type III in a Chinese girl and review of the genotype–phenotype spectrum. Mol Genet Genomic Med 2023:e2298. https://doi.org/10.1002/mgg3.2298.Search in Google Scholar PubMed PubMed Central

6. MacDonald, A, Van Wegberg, AMJ, Ahring, K, Beblo, S, Bélanger-Quintana, A, Burlina, A, et al.. PKU dietary handbook to accompany PKU guidelines. Orphanet J Rare Dis 2020;15:1–21. https://doi.org/10.1186/s13023-020-01391-y.Search in Google Scholar PubMed PubMed Central

7. Szymanska, E, Sredzinska, M, Ciara, E, Piekutowska-Abramczuk, D, Ploski, R, Rokicki, D, et al.. Tyrosinemia type III in an asymptomatic girl. Mol Genet Metab Rep 2015;5:48–50. https://doi.org/10.1016/j.ymgmr.2015.10.004.Search in Google Scholar PubMed PubMed Central

8. Thimm, E, Richter-Werkle, R, Kamp, G, Molke, B, Herebian, D, Klee, D, et al.. Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC. J Inherit Metab Dis 2012;35:263–8. https://doi.org/10.1007/s10545-011-9394-5.Search in Google Scholar PubMed

9. MacDonald, A, Ahring, K, Almeida, MF, Belanger-Quintana, A, Blau, N, Burlina, A, et al.. The challenges of managing coexistent disorders with phenylketonuria: 30 cases. Mol Genet Metabol 2015;116:242–51. https://doi.org/10.1016/j.ymgme.2015.10.001.Search in Google Scholar PubMed

10. Chen, S, Francioli, LC, Goodrich, JK, Collins, RL, Kanai, M, Wang, Q, et al.. A genomic mutational constraint map using variation in 76,156 human genomes. Nature 2024;625:92–100. https://doi.org/10.1038/s41586-023-06045-0.Search in Google Scholar PubMed PubMed Central

11. Adzhubei, IA, Schmidt, S, Peshkin, L, Ramensky, VE, Gerasimova, A, Bork, P, et al.. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–9. https://doi.org/10.1038/nmeth0410-248.Search in Google Scholar PubMed PubMed Central

12. Schwarz, JM, Cooper, DN, Schuelke, M, Seelow, D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014;11:361–2. https://doi.org/10.1038/nmeth.2890.Search in Google Scholar PubMed

13. Richards, S, Aziz, N, Bale, S, Bick, D, Das, S, Gastier-Foster, J, et al.. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med 2015;17:405–23. https://doi.org/10.1038/gim.2015.30.Search in Google Scholar PubMed PubMed Central

14. Coskun, T, Bilginer Gurbuz, B, Pektas, E, Yildiz, Y, Dursun, A, Sivri, HS, et al.. The first case of phenylketonuria with tyrosinemia type III [Abstract]. J Inherit Metab Dis 2016;39.Search in Google Scholar

Received: 2024-08-07

Accepted: 2024-12-10

Published Online: 2025-01-10

Published in Print: 2025-03-26

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/jpem-2024-0378

Keywords for this article

phenylketonuria; tyrosinemia type 3; coexistence; dietary management